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Gene expression profiling differentiates autism case–controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism

Authors

  • Valerie W. Hu,

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
    • Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, 2300 Eye St., N.W., Washington, DC 20037
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  • Tewarit Sarachana,

    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
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  • Kyung Soon Kim,

    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
    Current affiliation:
    1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
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  • AnhThu Nguyen,

    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
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  • Shreya Kulkarni,

    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
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  • Mara E. Steinberg,

    1. Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC
    Current affiliation:
    1. Department of Hearing and Speech Sciences, University of Maryland; College Park, MD 20742
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  • Truong Luu,

    1. Department of Pharmacology and Physiology, The George Washington University Medical Center, N.W., Washington, DC
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  • Yinglei Lai,

    1. Department of Statistics, The George Washington University, Washington, DC
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  • Norman H. Lee

    1. Department of Pharmacology and Physiology, The George Washington University Medical Center, N.W., Washington, DC
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Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.

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